Evidence for the LDL hypothesis raises new questions

Evidence for the LDL hypothesis raises new questions

Published online XX July 2015

In an article published on June 3, scientists have provided the best evidence yet that lowering low-density lipoprotein (LDL) levels improves cardiovascular health. The IMPROVE-IT trial helps to resolve a long-standing debate around the hypothesis that lowering LDL alone accounts for improved outcomes for patients taking statins. The alternative hypothesis posits that the effects of statins depend not only on lowering LDL, but also on unknown mechanisms.

IMPROVE-IT shows that lowering LDL in the bloodstream prevents cardiovascular disease. It also supports the idea that LDL levels alone are a good surrogate endpoint in clinical trials.

In the randomized study, 18,144 patients with acute coronary syndrome took the statin simvastatin plus ezetimibe (a drug that reduces intestinal absorption of cholesterol), or simvastatin plus a placebo. After 7 years, the group taking ezetimibe were significantly less likely to suffer from cardiovascular death, major coronary events or stroke, as opposed to those taking the placebo (32.7% versus 34.7%). In an editorial on the trial results, cardiologists John Jarcho and John Keaney Jr wrote “Perhaps the LDL hypothesis should now be considered the ‘LDL principle.’ ”

Settling this debate has consequences for the pharmaceutical industry, patients taking LDL-lowering drugs, and insurers paying for them. In June, a US Food & Drug Administration advisory committee recommended approval of a new class of drugs for which reduced LDL was the only clinical endpoint. The drugs, alirocumab and evolocumab, work by blocking the protein PCSK9. People naturally homozygous for PCSK9 mutations have extremely low levels of LDL and reduced risk of heart attack, even when they smoke or have high blood pressure.

The two PCSK9-blocking drugs clearly reduce LDL levels, but long-term data on endpoints such as death related to cardiovascular disease and on safety are lacking. As monoclonal antibodies, the drugs have drawbacks: they are expensive, which could have an enormous impact on healthcare costs; and they can be administered only by injection, which could hinder patients compliance.

Relatively few patients are expected to take PCSK9 blockers in the near future. But given the prevalence of deaths from cardiovascular disease and how potently these drugs reduce LDL levels, results from the IMPROVE-IT study could provide a powerful argument for much broader use.

For now, patients who take the new class of PDKC9 blockers – due to side effects from statins or poor response to them – are left with many questions. How low can LDL levels safely fall? What are the side effects? For patients responding to statins, are these more potent drugs a better option? Long-term clinical trials with outcome measurements such as those used in IMPROVE-IT may provide valuable answers.